Our lab is focused on molecular and cellular mechanisms that underlie virtually all major neurodegenerative diseases: the initiation and accumulation of highly ordered protein amyloids. We focus primarily on the tau protein, whose aggregation underlies neurodegeneration in Alzheimer's and other related diseases. We are using mechanistic knowledge to design more effective treatments and diagnostics. The same principles apply to other disease-causing proteins that form amyloid structures, such as α-synuclein and TDP-43.
We have discovered that tau shares essential characteristics with the human prion protein. This explains the relentless progression through brain networks, and phenotypic diversity of the myriad disorders termed "taupathies," which include Alzheimer's disease, the frontotemporal dementias, and chronic traumatic encephalopathy.
We use structural biology, biochemistry, and cell models to study fundamental events in pathogenesis, such as how pathological tau first forms distinct, self-replicating structures in each disease, and how an intracellular protein machinery mediates amplification of pathological forms. We are using detailed knowledge of tau's structure to engineer proteins that target its pathological conformations. We subsequently test predictions in mouse models.
Cell Biology
We have broken the pathogenic process down to its fundamental steps: cell binding, entry, replication/seeding, and release of seeds. We model each of these steps in a reductionist system.
We anticipate that this will allow us to identify new drug targets to interfere with tau prion replication.
Tau Strains
Tau amyloid structures that faithfully replicate in living systems are called "strains," which underlie unique patterns of pathology across the tauopathies.
Brain samples from patients with various neurodegenerative diseases yield different tau strains that, when introduced into mice, create distinct diseases.
These findings might lead to diagnostic tests to better identify and treat neurodegenerative diseases.
Protein Engineering for Therapy and Diagnosis
To target pathological conformations of tau we are developing biological agents that discriminate pathological from non-pathological structures. We are designing both active and passive vaccine strategies, and creating novel binding agents via nanobody engineering. Our goal is to use biological agents to detect and target pathological protein conformations.
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